Cholecystokinin (CCK) is a neuropeptide composed of thirty-three aminoacids in its originally isolated form. See: Mutt and Jorpes, Biochem. J. 125 678 (1971). Also occurring in circulation are 39, 12 and 8 amino acid forms. The carboxyl terminal octapeptide (CCK-8) is the minimum active sequence. Gastrin occurs in 34, 17, and 14 amino acid forms in circulation and is related to CCK by identity of the C-terminal pentapeptides Gly-Trp-Met-Asp-Phe-NH.sub.2. Gastrin and CCK exist in both gastrointestinal tissue and the central nervous system. V. Mutt, Gastrointenstinal Hormones, G. B. J. Glass, Ed., Raven Press, N.Y., p. 169 and G. Nisson, ibid, p. 127. CCK is believed to play an important role in appetite regulation and CCK may be a physiological satiety hormone. G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven Press, New York, 1984, p. 67.
Among additional effects of CCK are stimulation of colonic motility, stimulation of gall bladder contraction, stimulation of pancreatic enzyme secretion, and inhibition of gastric emptying. CCK reportedly co-exists with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain, as well as serving as a neurotransmitter in its own right. See: A. J. Prange et al., "Peptides in the Central Nervous System", Ann. Repts. Med. Chem. 17 31, 33 (1982) and reference cited therein; J. A. Williams, Biomed. Res. 3, 107 (1982); and J. E. Morley, Life Sci. 30, 479, (1982).
The primary role of gastrin appears to be stimulation of secretion of water and electrolytes from the stomach and it is therefore involved in control of gastric acid secretion.
CCK antagonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals, especially humans. Three distinct chemical classes of CCK receptor antagonists have been reported. One class comprises derivatives of cyclic nucleotides; detailed structure-function studies have demonstrated that of the various members of this class, dibutyryl cyclic GMP is the most potent. See; N. Barlos et al., Am. J. Physiol., 242, G 161 (1982) and P. Robberecht et al., Mol., Pharmacol., 17, 268 (1980). The second class comprises peptide antagonists which are C-terminal fragments and analogs of CCK. Recent structure-function studies have shown that both shorter C-terminal fragments of CCK (Boc-Met-Asp-Phe-NH.sub.2, Met-Asp-Phe-NH.sub.2) as well as longer CCK fragments Cbz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2) can function as CCK antagonists. See: R. T. Jensen et al., Biochem. Biophys. Acta., 757, 250 (1983) and M. Spanarkel et al., J. Biol. Chem., 258, 6746 (1983). The third class of CCK receptor antagonists comprises the amino acid derivatives; proglumide, a derivative of glutaramic acid, and the N-acyl tryptophans including para-chlorobenzoyl-L-tryptophan (benzotript). See W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) and R. T. Jensen et al., Biochem. Biophys. Acta., 761, 269 (1983). All of these compounds are relatively weak antagonists of CCK (IC.sub.50 : 10.sup.-4 -10.sup.-6 M; generally, 10.sup.-4 M but down to 10.sup.-6 M in the case of peptides). The peptide antagonists have substantial stability and absorption problems.
Gastrin antogonists are useful in the treatment and prevention of gastrin-related disorders of the gastrointestinal systems of humans and animals such as ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which reduced gastrin activity is of therapeutic value. There are no effective receptor antagonists of the in vivo effects of gastrin. J. S. Morley, Gut Pept. Ulcer Proc., Hiroshima Symp. 2nd, 1983, page 1. Very weak in vitro antagonists such as proglumide and certain peptides have been reported, J. Martinez, J. Med. Chem., 27, 1957 (1984).
The benzodiazepine (BZD) structure class has been widely exploited as therapeutic agents especially as central nervous system (CNS) drugs. These compounds exhibit strong binding to "benzodiazepine receptors" in vitro, but have not been reported to bind to CCK or gastrin receptors. The large majority of reported BZD's do not contain substituents attached to the 3-position of the seven-membered ring. It is well known in the art that 3-substituents result in decreasing CNS activity (non-CCK related), especially as these substituents increase in size. It has been demonstrated that the preferred stereochemistry at position 3 for this CNS activity is S, which would correspond to an L-amino acid such as L-tryptophan. The compounds of Formula I are distinguished from BZD's of the prior art especially by the presence of 3-substituents. The formula I compounds bind strongly to CCK receptors, but only weakly to BZD receptors, especially with increasing size of the substituents. The preferred stereochemistry of Formula I compounds is opposite to that of prior art BZD's.